The cytokine tumor necrosis factor‐α (TNF), well‐known for its roles in cellular responses to tissue injury, has recently been shown to be produced in response to physiological activity in neuronal circuits. TNF stimulates receptors in neurons linked to the activation of the transcription factor NF‐κB, and recent findings suggest that this signaling pathway can modulate neuronal excitability and vulnerability of neurons to excitotoxicity. Because data indicate that TNF is produced, and NF‐κB activated, under conditions associated with learning and memory, we performed experiments in the hippocampal slice preparation aimed at elucidating roles for TNF and NF‐κB in modulating synaptic plasticity. Whereas stimulation of Schaffer collateral axons at a frequency of 1 Hz induced long‐term depression (LTD) of synaptic transmission in region CA1 of wild‐type mice, LTD did not occur in slices from TNF receptor knockout mice. Stimulation at 100 Hz induced long‐term potentiation (LTP) in slices from both wild‐type mice and mice lacking TNF receptors. Basal transmission was unaltered in mice lacking TNF receptors. Pretreatment of slices from wild‐type mice with κB decoy DNA prevented induction of LTD and significantly reduced the magnitude of LTP. Collectively, these data suggest important roles for TNF and signaling pathways that modulate NF‐κB activity in regulation of hippocampal synaptic plasticity. Synapse 35:151–159, 2000. © 2000 Wiley‐Liss, Inc.